Cyclic hemiketal

In a similar manner, ketones can react with alcohols to form hemiketals. The analogous intramolecular reaction of a ketose sugar such as fructose yields a cyclic hemiketal (Figure 7.6). The five-membered ring thus formed is reminiscent of furan and is referred to as a furanose. The cyclic pyranose and fura-nose forms are the preferred structures for monosaccharides in aqueous solution. At equilibrium, the linear aldehyde or ketone structure is only a minor component of the mixture (generally much less than 1%). 

The enantioselective reduction of unsaturated alcohol derivatives has been applied to the synthesis of several biologically active compounds (Scheme 24.12). Warfarin (123, R=H) is an important anticoagulant that is normally prescribed as the racemate, despite the enantiomers having dissimilar pharmacological profiles. One of the earliest reported uses of DuPhos was in the development of a chiral switch for this bioactive molecule, facilitating the preparation of (R)- and (S)-warfarin [184]. Although attempted reduction of the parent hydroxycoumarin 122 (R=H) led to formation of an unreactive cyclic hemiketal, hydrogenation of the sodium salt proceeded smoothly with Rh-Et-DuPhos in 86-89% ee. 

Warfarin, 3-(l-phenyl-3-oxobutyl)-4-hydroxycoumarin (51 R = Ph R = H), is a clinically useful oral anticoagulant drug, which exists in two diastereomeric cyclic hemiketal forms and as the open-chain ketone (51B - SIA SIC) (84JMO1092 90MI3). Table VIII shows that the intro-... 

The laC data indicate clearly that warfarin is not 15 in solution but is a mixture of two diastereoisomers (16 and 17, called cyclic hemiketals) resulting from addition of the —OH group of 15 to the C=0 bond ... 

Five- or six-membered cyclic hemiketals, which are also referred to as lactols, can form from y- or 8-hydroxy kefones. However, hemiketals of this type are not necessarily more stable than the acyclic hydroxyketone isomers because ketones are less thermodynamically suitable to add nucleophiles than are aldehydes (Section 9.1.1). 

As already mentioned, <5-hydroxyfeto s may be present in the open-chain form or as an isomeric cyclic hemiketal, depending on their substitution pattern. For example, a polyhy-droxylated 5-hydroxyketone, D-fructose, is present exclusively in the form of hemiketals (Figure 9.7). Responsible for this equilibrium position is the fact that the carbonyl group involved contains an electron-withdrawing group in both a-positions, which favors the addition of nucleophiles (see Section 9.1.1). 

In 1993, Molander found that in the presence of catalytic Fe(III) salts, Sml2 mediates intramolecular Barbier additions to esters to give cyclic ketones (or cyclic hemiketals, if they prove to be stable).135 Double addition to the ester is not observed, nor is reduction of the cyclic ketone product. This suggests that the tetrahedral intermediate, a samarium alkoxide of a cyclic hemiketal, is partially stable to the reaction conditions and the ketone group is not revealed until work-up. Molander found that both alkyl and allyl halides could be used in the additions (Scheme 5.83).135... 

Enders D, Dyker H, Raabe G, Runsink J (1992) Enantio- and diastereoselec-tive synthesis of 3-substituted cyclic hemiketals of a>-hydroxy-2-oxoesters. Synlett 1992 901-903... 

The C-2 keto group in the open-chain form of a ketohexose, such as fructose, can form an intramolecular hemiketal by reacting with either the C-6 hydroxyl group to form a six-membered cyclic hemiketal or the C-5 hydroxyl group to form a five-membered cyclic hemiketal (Figure 11.5). The five-membered ring is called a furanose because of its similarity to... 

Given its therapeutic importance as an anticoagulant, it is surprising that the literature lacks a catalytic asymmetric synthesis of the bioactive R-warfarin it is normally prescribed as the racemate. On attempted hydrogenation of the direct alkene precursor the parent hydroxycoumarin forms an unreactive cyclic hemiketal. Hence the reduction is performed on the sodium salt or on the 4-meth-oxycoumarin, and with S,S-Rh(EtDUPHOS) occurs in 86-89% ee [102]. 

Because the resolution with acylase gave a theoretical maximum yield of only 50% and required separation of the desired product from the unreacted enantiomer at the end of the reaction, we next tried to prepare the amino acid by reductive amination of the corresponding ketoacid, a process with a theoretical maximum yield of 100%. A variety of ketoacids can be converted to L-amino acids by treatment with ammonia, reduced nicotinamide adenine dinucleotide (NADH), and a suitable amino acid dehydrogenase. 2-Keto-6-hydroxyhexanoic acid (in equilibrium with its cyclic hemiketal form) was prepared by chemical synthesis starting from 4-chloro-l-butanol, which was... 

In CF3COOH the allenic end group of neoxanthin (38) is converted to the acetylenic end group [80] and with concentrated HC1, a chloride is added to the allene [10]. The blue oxonium ion 40 is converted to a yellow, cyclic hemiketal 41 by treatment with KOH. The hemiketal 41 is... 

Fig. (17). Formation of blue oxonium ions via cyclic hemiketals upon treatment of fucoxanthin (42) with strong acid, and conversion of the blue oxonium ion to yellow hemiketal with base Reprinted with permission from [10], Copyright 1994 Acta Chemica Scandinavica.

Sugars, especially those with five or six carbon atoms, normally exist as cyclic molecules rather than as the open-chain forms we have shown so far. The cycUzation takes place as a result of interaction between the functional groups on distant carbons, such as G-1 and G-5, to form a cyclic hemiacetal (in aldohexoses). Another possibility (Figure 16.5) is interaction between G-2 and G-5 to form a cyclic hemiketal (in ketohexoses). In either case, the carbonyl carbon becomes a new chiral center called the anomeric carbon. The cyclic sugar can take either of two different forms, designated a and P, and are called anomers of each other. 

Ketohexoses such as o-fructose also exist as cyclic compounds. Addition of the OH at C-5 to the carbonyl group forms the 5-membered cyclic hemiketal (Fig. 18-4). The 5-membered ring is often referred to as a furanose ring. The a- and /3-notations are the same as for o-glucose. The OH groups at C-2 in a-o-fructose and /S-D-fructose are irons and cis, respectively, to the CH2OH at C-5. 

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